Hsu Hung-Chih, You Jeng-Fu, Chen Shu-Jen, Chen Hua-Chien, Yeh Chien-Yuh, Tsai Wen-Sy, Hung Hsin-Yuan, Yang Tsai-Sheng, Lapke Nina, Tan Kien Thiam
Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan.
College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan.
Cancers (Basel). 2019 Jul 30;11(8):1079. doi: 10.3390/cancers11081079.
(1) Background: Bevacizumab-based regimens are a standard treatment for metastatic colorectal cancer (mCRC) patients, however meaningful clinical biomarkers for treatment benefit remain scarce. (2) Methods: Tumor samples from 36 mCRC patients treated with bevacizumab-based chemotherapy underwent comprehensive genomic profiling. Alterations in frequently altered genes and important signaling pathways were correlated with progression-free survival (PFS). (3) Results: Overall genetic alteration analysis of investigated genes and pathways did not identify promising new predictors of PFS. However, when considering mutation subtypes, DNA binding domain (DBD) missense mutations were associated with prolonged PFS (HR, 0.41; 95% CI, 0.13-0.65; = 0.005). In contrast, truncating mutations were associated with short PFS (HR, 2.95; 95% CI, 1.45-27.50; = 0.017). Importantly, neither mutation subtype was associated with overall response rate. In multivariate analysis, DBD missense mutations remained an independent PFS predictor (HR, 0.31; 95% CI, 0.13-0.77; = 0.011). The other genetic factor independently associated with PFS were deleterious alterations, which we previously identified in a screen for biomarkers of bevacizumab response. (4) Conclusions: DBD missense mutations may predict prolonged PFS in mCRC patients treated with bevacizumab-based therapy. Analyses of mutations as clinical biomarkers should take the biological impact of different mutation subtypes into consideration to improve patient stratification.
(1) 背景：基于贝伐单抗的治疗方案是转移性结直肠癌（mCRC）患者的标准治疗方法，然而，能表明治疗获益的有意义的临床生物标志物仍然很少。(2) 方法：对36例接受基于贝伐单抗化疗的mCRC患者的肿瘤样本进行全面的基因组分析。频繁改变的基因和重要信号通路的改变与无进展生存期（PFS）相关。(3) 结果：对所研究基因和通路的总体基因改变分析未发现有前景的PFS新预测因子。然而，考虑突变亚型时，DNA结合域（DBD）错义突变与PFS延长相关（HR，0.41；95%CI，0.13 - 0.65；P = 0.005）。相比之下，截断突变与PFS缩短相关（HR，2.95；95%CI，1.45 - 27.50；P = 0.017）。重要的是，两种突变亚型均与总体缓解率无关。在多变量分析中，DBD错义突变仍然是独立的PFS预测因子（HR，0.31；95%CI，0.13 - 0.77；P = 0.011）。另一个与PFS独立相关的遗传因素是有害改变，这是我们之前在贝伐单抗反应生物标志物筛选中发现的。(4) 结论：DBD错义突变可能预测接受基于贝伐单抗治疗的mCRC患者PFS延长。将突变作为临床生物标志物进行分析时，应考虑不同突变亚型的生物学影响，以改善患者分层。
